Unfavorable Role Research Articles

Granzyme A impairs host defense during Streptococcus pneumoniae pneumonia.

Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia (CAP). Granzyme A (GzmA) is a serine protease produced by a variety of cell types involved in the immune response. We sought to determine the role of GzmA on the host response during pneumococcal pneumonia. GzmA was measured in bronchoalveolar lavage fluid (BALF) harvested from CAP patients from the infected and contralateral uninfected side and in lung tissue slides from CAP patients and controls. In CAP patients, GzmA levels were increased in BALF obtained from the infected lung. Human lungs showed constitutive GzmA expression by both parenchymal and nonparenchymal cells. In an experimental setting, pneumonia was induced in wild-type (WT) and GzmA-deficient (GzmA(-/-)) mice by intranasal inoculation of S. pneumoniae In separate experiments, WT and GzmA(-/-) mice were treated with natural killer (NK) cell depleting antibodies. Upon infection with S. pneumoniae, GzmA(-/-) mice showed a better survival and lower bacterial counts in BALF and distant body sites compared with WT mice. Although NK cells showed strong GzmA expression, NK cell depletion did not influence bacterial loads in either WT or GzmA(-/-) mice. These results implicate that GzmA plays an unfavorable role in host defense during pneumococcal pneumonia by a mechanism that does not depend on NK cells.

Caspase-1 Deficiency Alleviates Dopaminergic Neuronal Death via Inhibiting Caspase-7/AIF Pathway in MPTP/p Mouse Model of Parkinson's Disease.

Caspase family has been recognized to be involved in dopaminergic (DA) neuronal death and to exert an unfavorable role in Parkinson's disease (PD) pathology. Our previous study has revealed that caspase-1, as an important component of NLRP3 inflammasome, induces microglia-mediated neuroinflammation in the pathogenesis of PD. However, the role of caspase-1 in DA neuronal degeneration in the onset of PD remains unclear. Here, we showed that caspase-1 knockout ameliorated DA neuronal loss and dyskinesia in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p)-induced PD model mice. We further found that caspase-1 knockout decreased MPTP/p-induced caspase-7 cleavage, subsequently inhibited nuclear translocation of poly (ADP-ribose) polymerase 1 (PARP1), and reduced the release of apoptosis-inducing factor (AIF). Consistently, we demonstrated that caspase-1 inhibitor suppressed caspase-7/PARP1/AIF-mediated apoptosis pathway by 1-methyl-4-phenylpyridinium ion (MPP+) stimulation in SH-SY5Y cells. Caspase-7 overexpression reduced the protective effects of caspase-1 inhibitor on SH-SY5Y cell apoptosis. Collectively, our results have revealed that caspase-1 regulates DA neuronal death in the pathogenesis of PD in mice via caspase-7/PARP1/AIF pathway. These findings will shed new insight into the potential of caspase-1 as a target for PD therapy.

Breast-conserving treatment for ductal carcinoma in situ: Impact of boost and tamoxifen on local recurrences

PurposeDuctal carcinoma in situ represents 15 to 20% of all breast cancers. Breast-conserving surgery and whole breast irradiation was performed in about 60% of the cases. This study reports local recurrence rates in patients with ductal carcinoma in situ treated by breast-conserving surgery and whole breast irradiation with or without boost and/or tamoxifen and compares different therapeutic options in two European countries. Patients and methodsFrom 1998 to 2007, 819 patients with pure ductal carcinoma in situ were collected, both in France (266) and Italy (553). Median age was 56. All underwent breast-conserving surgery and whole breast irradiation; 391 (48%) received a boost (55% in France and 45% in Italy, P=0.017) and 173 (22.5%) tamoxifen (4.5% in France and 32% in Italy, P<0.0001). ResultsWith a 90-month median follow-up, there were 51 local recurrences (6.2%), including 27 invasive (53%). The 5- and 10-year local recurrence rates were 4% and 8.6%. Two patients developed axillary recurrence and 12 (1.5%) metastases (seven after invasive local recurrence); 41 (5%) patients had contralateral breast cancer. In the multivariate analysis, high nuclear grade and lack of tamoxifen are the most powerful predictors of local recurrence, with 2.6 (95% confidence interval [95% CI]: 1.74–3.89, P=0.0012) and 2.85 (95% CI: 1.42–5.72, P=0.04) odds ratio (OR) estimates, respectively. Age, margin status and boost did not influence local recurrence rates. ConclusionsThis study confirms the ductal carcinoma in situ treatment heterogeneity among countries and the unfavourable prognostic role of nuclear grade. Tamoxifen reduces local recurrence rates and might be considered for some subgroups of patients, but further confirmation is required. The boost usefulness still remains unclear.

Increased expression of LncRNA PANDAR predicts a poor prognosis in gastric cancer.

Long non-coding RNAs (lncRNAs) are emerging as biomarkers and as important regulators in biological processes and tumorigenesis in cancer. PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) serves as biomarkers and involves in development of multiple cancers. However, its clinical value of PANDAR in gastric cancer is still unknown. Hence, we carried out the present study aiming to identify the clinical significance of PANDAR in gastric cancer patients. We analyzed the expression levels of PANDAR in 100 paired gastric cancer tissues using Quantitative Real-time PCR. Our results showed that the expression of PANDAR was significantly increased in gastric cancer tissues compared with paired adjacent normal tissues. Furthermore, high expression of PANDAR was correlated with depth of invasion, TNM stage and lymphatic metastasis. Importantly, high expression of PANDAR could serve as an independent unfavorable prognostic role in gastric cancer. In conclusion, PANDAR may be a potential novel biomarker that predicts prognosis in gastric cancer.

IL-27 Promotes Proliferation of Human Leukemic Cell Lines Through the MAPK/ERK Signaling Pathway and Suppresses Sensitivity to Chemotherapeutic Drugs.

IL-27 is a pleiotropic cytokine of the IL-6/IL-12 family with diverse biological functions. Previous in vivo studies have suggested the antitumor activities of IL-27 in animal models, whereas clinical observations indicate the link of IL-27 in tumor progression. IL-27 has recently been shown to cause inhibition of proliferation on primary leukemic cells from pediatric patients, but information on its role in human leukemic cell lines is limited. In the present study, we investigated the ability of IL-27 to regulate cell growth and survival of various human leukemic cell lines. Our results showed that in human leukemic cell lines coexpressing both IL-27R chains, IL-27Rα and gp130, IL-27 did not inhibit cell growth, but caused dose-dependent proliferation of the acute myeloid leukemic cell line, OCI-AML5, and the erythroleukemic cell lines, TF-1, UT-7, and UT-7/EPO. Consistent with this, IL-27 promoted cell survival and reduced TNF-α-induced apoptosis of the leukemic cell lines. IL-27 also decreased the responsiveness of the leukemic cells to chemotherapeutic drugs, cytarabine and daunorubicin. We observed that IL-27 induced the activation of STAT1/3 and ERK1/2 in the leukemic cells. Growth stimulation by IL-27 was suppressed by the specific MEK inhibitor, U0126, indicating that IL-27-induced cell proliferation is mainly mediated through the activation of the MAPK/ERK signaling pathway. The present study is the first demonstration of the proliferative and antichemotherapeutic properties of IL-27 in human leukemic cell lines, suggesting that IL-27 can play an unfavorable role in tumor growth and can be an important determinant in the chemoresponsiveness of certain subtypes of human leukemia.

Revealing the unfavorable role of superfluous CH3NH3PbI3 grain boundary traps in perovskite solar cells on carrier collection

In this work, the perovskite films with controllable grain size are obtained by a facile method. And the unfavorable role of perovskite grain boundary traps is unveiled by the combination of experiment and simulation analysis.

Prognostic Role of Multiple Lymphatic Basin Drainage in Sentinel Lymph Node-Negative Trunk Melanoma Patients: A Multicenter Study from the Italian Melanoma Intergroup.

Multiple lymphatic basin drainage (MLBD) is frequently observed in patients with trunk melanoma undergoing sentinel lymph node (SLN) biopsy. Conflicting data regarding the prognostic association of MLBD in SLN-negative patients have been reported. This study aimed to investigate the prognostic role of MLBD in patients with negative SLN biopsy. Retrospective data from 656 melanoma patients who underwent a SLN biopsy (1991-2012) at six Italian centers were gathered in a multicenter database. MLBD was defined as lymphoscintigraphic and intraoperative identification of an SLN in more than one nodal basin. Clinical and pathologic variables were recorded and analyzed for their impact on survival. SLN-negative patients with MLBD were at lower risk of melanoma recurrence [hazard ratio (HR) 0.73, P=0.05) and melanoma-related death (HR 0.68, P=0.001) independent of common staging features. Multivariable Cox analyses of disease-free interval (DFI) and disease-specific survival (DSS) showed that MLBD maintained a favorable role and ulceration an unfavorable role. Histologic regression was independently associated only with DFI. When survival was stratified according to presence of MLBD, histologic regression and Breslow thickness <2mm were associated with improved DFI (5-year DFI: 96.9 vs. 66,1%, respectively; HR 0.48, P<0.001) and DSS (5-year DSS: 96.7 vs. 71.8%, respectively; HR 0.52, P=0.005) compared to patients without these three favorable parameters. Patients with negative SLN biopsy results have better prognosis when two or more lymphatic basins are identified and analyzed. Further research is required to investigate the mechanisms behind this evidence.

ID: 18: IL-27 promotes cell proliferation and survival of human leukemic cell lines through activation of the MAPK/ERK and PI3K/AKT signalling pathways

IL-27 is a pleiotropic cytokine of the IL-6/IL-12 family with diverse biological functions. Previous in vivo studies have suggested the anti-tumour activities of IL-27 in animal models, whereas clinical observations indicate the link of IL-27 in tumour progression. IL-27 has recently been shown to cause inhibition of proliferation on primary leukemic cells from paediatric patients, but information on its role in human leukemic cell lines is limited. In the present study, we investigated the ability of IL-27 to regulate cell growth and survival of various human leukemic cell lines. Our results showed that in human leukemic cell lines coexpressing both IL-27R chains IL-27R α and gp130, IL-27 did not inhibit cell growth, but caused a dose-dependent proliferation of the acute myeloid leukemic cell line OCI-AML5, and the erythroleukemic cell lines, TF-1, UT-7 and UT7/EPO. Consistent with this, IL-27 promoted cell survival and reduced TNF- α -induced apoptosis of the leukemic cell lines. IL-27 also decreased the sensitivity of the leukemic cells to chemotherapeutic drugs cytarabine and daunorubicin. We observed that IL-27 induced the activation of STAT1/3 and ERK1/2 in the leukemic cells. Growth stimulation by IL-27 was suppressed by the specific MEK inhibitor U0126 and the PI3K inhibitor wortmannin, suggesting that IL-27-induced cell proliferation is mediated via the activation of two distinct pathways of MAPK/ERK and PI3K/AKT. The present study is the first demonstration of the proliferative property of IL-27 in human leukemic cell lines, suggesting that IL-27 may play an unfavourable role in tumour growth of certain subtypes of human leukaemia.

Enhanced IL-6 trans-signaling in pulmonary arterial hypertension and its potential role in disease-related systemic damage

BackgroundThe role of IL-6 in pulmonary arterial hypertension (PAH) has been reported but the prevalence of soluble receptors for IL-6: sIL-6R and sgp130 and its potential role in PAH have not been studied.Our aim was to examine the IL-6 together with the soluble receptors and to assess its relationship with clinical status of PAH patients as well as to assess its potential prognostic significance. MethodsSerum concentrations of IL-6, sIL-6R and sgp130 were quantified by ELISA in 26 patients with PAH and 27 healthy controls and related to functional and biochemical parameters and clinical outcome in PAH group. The PAH patients were followed up for 1year, noting the end point of clinical deterioration (WHO class change, the need for escalation of therapy) or death. ResultsThe PAH group was characterized by higher median serum IL-6 [2.38 (IQR 1.56–3.75) vs 0.87 (0.63–1.3)pg/ml, p=0.000003] and sIL-6R concentrations [69.7 (IQR 60.4–84.4 vs 45.7 (34.6–70.3)ng/ml, p=0.0036] compared to control subjects. Both groups did not differ in sgp130 concentrations. There were significant correlations in PAH group between IL-6 levels and uric acid, parameters of ventilatory efficiency in cardiopulmonary exercise testing: VE/VO2, VE/VCO2, VE/VCO2 slope and peak PetCO2. sIL-6R levels inversely correlated with LDL cholesterol. After 1year the clinical deterioration occurred in 11 patients, 15 remained stable. Patients in whom the clinical deterioration occurred showed significantly higher baseline concentrations of IL-6 [3.25 (IQR 2.46–5.4)pg/ml vs 1.68 (1.38–2.78)pg/ml, p=0.004], but not sIL-6R. Median IL-6⩾2.3pg/ml (91% sensitivity, 73% specificity) identified subjects with worse clinical course. In the univariate analysis, higher IL-6 level at baseline was associated with increased risk and earlier occurrence of clinical deterioration (HR 1.42, 95%CI 1.08–1.85, p=0.015). ConclusionsIL-6 trans-signaling is enhanced in PAH. Elevated concentration of sIL-6R suggests its potential unfavorable role in systemic amplification of IL-6 signaling in PAH. Levels of IL-6 are associated with clinical indicators of disease severity as well as indirectly with systemic metabolic alterations. IL-6 shows prognostic value regarding predicting clinical deterioration.

English

The over exploitation of Nauclea diderrichii, for its very resistant wood against the attacks of fungus (Coriolus versicolor), Lyctus, termites (Reticulitermes santonensis) and marine borers, leads to its disappearance in Togo. This forest species produces many fruits containing numerous seeds; unfortunately their seedling is laborious in its biotope. In vitro micropropagation trials were carried out for a faster and massive regeneration. The effect of carbon source on the rooting and the growth of seedlings were studied in the presence of sucrose, glucose, fructose, mannitol, maltose, galactose, mannose, lactose, sorbose and sorbitol. Woody plant medium (WPM) of Lloyd and McCown has been used. This medium was modified by supply of microelements and vitamins of Murashige and Skoog and supplemented by 30 g/L of these carbohydrates. The best plants&rsquo; growth and rooting were obtained with sucrose. Sucrose appears to be the most favorable sugar to ensure the in vitro micropropagation of N. diderrichii. Sorbose caused the necrosis of explants in culture. The mannose and the mannitol, did not cause the necrosis of explants, but their presence had an unfavorable role on roots initiation and slow down the plants&rsquo; growth. &nbsp; Key words: Sources of carbon, Nauclea diderrichii, in vitro micropropagation, Togo.

Mitochondrial estrogen receptor β2 drives antiapoptotic pathways in advanced serous ovarian cancer.

We previously showed an unfavorable prognostic role of the cytoplasmic estrogen receptor β2 (cERβ2) in serous ovarian cancer. Here we aimed to investigate molecular determinants in cell survival function of cERβ2 in this malignant disease. We used immunohistochemistry to evaluate differences in apoptosis (quantified by the expression of cleaved caspase-3) and cell proliferation (quantified by the expression of Ki-67) in 56 advanced serous ovarian cancer cases, stratified according to the absence or presence of estrogen receptor β2 (ERβ2) protein in the cytoplasmic compartment (31 cERβ2- and 25 cERβ2+ cases, respectively). Thereafter, by immunofluorescence, we visualized the subcellular distribution of ERβ2, and by the proximity ligation assays, we characterized in situ its ability to interact with other proteins specifically involved in the apoptosis cascade. Finally, we assessed cytochrome c expression by immunohistochemistry. We demonstrated that, although not affecting tumor proliferation, cytoplasmic ERβ2 expression was indeed associated to a lower apoptotic rate in ovarian cancer cases. Then, we proved that cERβ2 is targeted to mitochondria where it interacts as a binding partner with BAD (B-cell lymphoma [Bcl] 2-associated death promoter). This interaction, precluding the Bcl-xL (B-cell lymphoma extra large)/BAD heterodimer formation, inhibited Bax (Bcl-2-like protein 4) oligomerization, the release of cytochrome c, and ultimately apoptosis. In conclusion, we provide in vivo mechanistic evidence for an antiapoptotic function of mitochondrial ERβ2, a finding supporting the value of its cytoplasmic expression as an unfavorable prognostic biomarker for serous ovarian cancer.

Design and Evaluation of 3-(Benzylthio)benzamide Derivatives as Potent and Selective SIRT2 Inhibitors.

Inhibitors of sirtuin-2 (SIRT2) deacetylase have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the 3-(benzylsulfonamido)benzamide scaffold and improving their metabolic stability. Molecular modeling and docking studies revealed an unfavorable role of the sulfonamide moiety for SIRT2 binding. This prompted us to replace the sulfonamide with thioether, sulfoxide, or sulfone groups. The thioether analogues were the most potent SIRT2 inhibitors with a two- to three-fold increase in potency relative to their corresponding sulfonamide analogues. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. Two thioether-derived compounds (17 and 18) increased α-tubulin acetylation in a dose-dependent manner in at least one neuronal cell line, and 18 was found to inhibit polyglutamine aggregation in PC12 cells.

Knockdown of SALL4 Protein Enhances All-trans Retinoic Acid-induced Cellular Differentiation in Acute Myeloid Leukemia Cells

All-trans retinoic acid (ATRA) is a differentiation agent that revolutionized the treatment of acute promyelocytic leukemia. However, it has not been useful for other types of acute myeloid leukemia (AML). Here we explored the effect of SALL4, a stem cell factor, on ATRA-induced AML differentiation in both ATRA-sensitive and ATRA-resistant AML cells. Aberrant SALL4 expression has been found in nearly all human AML cases, whereas, in normal bone marrow and peripheral blood cells, its expression is only restricted to hematopoietic stem/progenitor cells. We reason that, in AMLs, SALL4 activation may prevent cell differentiation and/or protect self-renewal that is seen in normal hematopoietic stem/progenitor cells. Indeed, our studies show that ATRA-mediated myeloid differentiation can be largely blocked by exogenous expression of SALL4, whereas ATRA plus SALL4 knockdown causes significantly increased AML differentiation and cell death. Mechanistic studies indicate that SALL4 directly associates with retinoic acid receptor α and modulates ATRA target gene expression. SALL4 is shown to recruit lysine-specific histone demethylase 1 (LSD1) to target genes and alter the histone methylation status. Furthermore, coinhibition of LSD1 and SALL4 plus ATRA treatment exhibited the strongest anti-AML effect. These findings suggest that SALL4 plays an unfavorable role in ATRA-based regimes, highlighting an important aspect of leukemia therapy.

Unfavorable effect of small tumor size on cause-specific survival in stage IIA colon cancer, a SEER-based study.

We sought to determine the prognostic role of tumor size on cause-specific survival (CSS) of patients with stage IIA colon cancer. Surveillance, Epidemiology and End Results (SEER) database was utilized to identify patients with stage IIA colorectal cancer (examined lymph nodes ≥12) diagnosed from 1988 to 2003. The prognostic effect of tumor size on CSS was evaluated by univariate and multivariate analyses. A total of 8775 patients were enrolled in the analysis. The median follow-up time was 109 months. As determined by minimal P value method, tumor sizes of 2.5 and 6.0 cm were used as optimal cutoff value to divide the cohort. The 8-year CSS of colon cancer with tumor sizes ≤2.5, 2.6-6.0, and >6.0 cm was 81.6, 86.2, and 86.7% respectively (P = 0.003). In the multivariate analysis of colon cancer, using ≤2.5-cm tumors as reference, decreased hazard ratio (HR) of CSS was observed in 2.6-6.0 cm (HR, 0.736; 95% confidence interval (CI), 0.599-0.905; P = 0.004) and >6.0 cm (HR, 0.770; 95% CI, 0.619-0.958; P = 0.019) tumors. In stage IIA colon cancer, small tumor size represented a subset with decreased CSS. Further studies are merited to validate the unfavorable prognostic role of small tumor size in stage IIA colon cancer.

The dual role of scavenger receptor class A in development of diabetes in autoimmune NOD mice.

Human type 1 diabetes is an autoimmune disease that results from the autoreactive destruction of pancreatic β cells by T cells. Antigen presenting cells including dendritic cells and macrophages are required to activate and suppress antigen-specific T cells. It has been suggested that antigen uptake from live cells by dendritic cells via scavenger receptor class A (SR-A) may be important. However, the role of SR-A in autoimmune disease is unknown. In this study, SR-A−/− nonobese diabetic (NOD) mice showed significant attenuation of insulitis, lower levels of insulin autoantibodies, and suppression of diabetes development compared with NOD mice. We also found that diabetes progression in SR-A−/− NOD mice treated with low-dose polyinosinic-polycytidylic acid (poly(I∶C)) was significantly accelerated compared with that in disease-resistant NOD mice treated with low-dose poly(I∶C). In addition, injection of high-dose poly(I∶C) to mimic an acute RNA virus infection significantly accelerated diabetes development in young SR-A−/− NOD mice compared with untreated SR-A−/− NOD mice. Pathogenic cells including CD4+CD25+ activated T cells were increased more in SR-A−/− NOD mice treated with poly(I∶C) than in untreated SR-A−/− NOD mice. These results suggested that viral infection might accelerate diabetes development even in diabetes-resistant subjects. In conclusion, our studies demonstrated that diabetes progression was suppressed in SR-A−/− NOD mice and that acceleration of diabetes development could be induced in young mice by poly(I∶C) treatment even in SR-A−/− NOD mice. These results suggest that SR-A on antigen presenting cells such as dendritic cells may play an unfavorable role in the steady state and a protective role in a mild infection. Our findings imply that SR-A may be an important target for improving therapeutic strategies for type 1 diabetes.

THE IMPACT OF EMPLOYEE MOTIVATION ON SERVICE QUALITY AND COMMUNITY SATISFACTION WITHIN PUBLIC SERVICE QUALITY IN THE DISTRICT OF SOUTH TANGERANG

South Tangerang is a new autonomous region in Banten Province that is established by Act No. 51 of 2008. The new autonomous region in Banten as expansion of Tangerang Regency has 7 districts. Based on Population Census in 2014 has 1.405.170 inhabitants. Population of male is 708.767 inhabitants and population of female is 696.403 inhabitants. Information found directly and through various media frequently reveals weaknesses of government services which reflect community dissatisfaction with the service personnel. The level of community satisfaction with the services of the community sector is still quite low, it is evidenced from several empirical studies on the quality of service in local government bureaucracy. Based on the initial observation, work motivation of goverment officials is played a role in realizing the quality of public services in the district of South Tangerang. Hence the author is interested in further researching and analyzing the impact of work motivation and service quality of apparatus to satisfaction community in the district level of South Tangerang. This study use nonprobability sampling as the sampling method. For the purposes of quantitative analysis, the determination of the score for each item questionnaire is used a Likert Scale. The processing data in this study is using SEM with support of software LISREL 8.7. The result of study shows that the motivation of civil servants apparatus district in South Tangerang is affecting the quality of service however is not affecting community satisfaction. This is due to the unfavorable work environment and leadership role in the completion of the assignment. Meanwhile the quality of service of civil servants apparatus affects people's satisfaction in districts in South Tangerang.

SP0192 Energy Metabolism and Chronic Inflammatory Rheumatic Diseases

The general meaning of the systemic response in inflammatory diseases is not well understood. Nor do we know whether the systemic response has any unfavorable role when inflammatory diseases become...

Mast cells impair host defense during murine Streptococcus pneumoniae pneumonia.

Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia. Mast cells (MCs) are located mainly at the host-environment interface where they function as sentinels. Our goal was to study the role of MCs during pneumonia caused by S. pneumoniae. Lung tissue of patients who had died from pneumococcal pneumonia or a nonpulmonary cause was stained for MCs and tryptase. Wild-type (WT) and MC-deficient (Kit(W-sh/W-sh)) mice were observed or sacrificed after induction of pneumonia by intranasal inoculation of S. pneumoniae. In separate experiments, WT mice were treated with doxantrazole or cromoglycate, which are MC stabilizing agents. The constitutive presence of tryptase-positive MCs was reduced in affected lungs from pneumonia patients. Kit(W-sh/W-sh) mice showed a prolonged survival during the first few days after median lethal dose (LD)100 and LD50 infection, while overall mortality did not differ from that in WT mice. Relative to WT mice, Kit(W-sh/W-sh) mice showed reduced bacterial counts with less bacterial dissemination to distant organs and less inflammation. Neither doxantrazole nor cromoglycate influenced antibacterial defense or inflammatory responses after airway infection with S. pneumoniae. MCs exhibit an unfavorable role in host defense during pneumococcal pneumonia by a mechanism independent of degranulation.

Subtype-dependent prognostic relevance of an interferon-induced pathway metagene in node-negative breast cancer

The majority of gene expression signatures developed to predict the likelihood to relapse in breast cancer (BC) patients assigns a high risk score to patients with Estrogen Receptor (ER) negative or highly proliferating tumors. We aimed to identify a signature of differentially expressed (DE) metagenes, rather than single DE genes, associated with distant metastases beyond classical risk factors.We used 105 gene expression profiles from consecutive BCs to identify metagenes whose prognostic role was defined on an independent series of 92 ESR1+/ERBB2− node-negative BCs (42 cases developing metastases within 5 years from diagnosis and 50 cases metastasis-free for more than 5 years, comparable for age, tumor size, ER status and surgery). Findings were validated on publicly available datasets of 684 node-negative BCs including all the subtypes.Only a metagene containing interferon-induced genes (IFN metagene) proved to be predictive of distant metastasis in our series of patients with ESR1+/ERBB2− tumors (P = 0.029), and such a finding was validated on 457 ESR1+/ERBB2− BCs from public datasets (P = 0.0424). Conversely, the IFN metagene was associated with a low risk of metastasis in 104 ERBB2+ tumors (P = 0.0099) whereas it did not prove to significantly affect prognosis in 123 ESR1−/ERBB2− tumors (P = 0.2235). A complex prognostic interaction was revealed in ESR1+/ERBB2− and ERBB2+ tumors when the association between the IFN metagene and a T-cell metagene was considered.The study confirms the importance of analyzing prognostic variables separately within BC subtypes, highlights the advantages of using metagenes rather than genes, and finally identifies in node-negative ESR1+/ERBB2− BCs, the unfavorable role of high IFN metagene expression.

Association between atopy, mastoid pneumatization and tympanometric findings

The purpose of this study was to reveal whether the presence of atopy plays any unfavorable role in the development of a healthy middle ear as evaluated by tympanometry or in the degree of mastoid pneumatization as measured by mastoid volume. 33 atopic patients with positive skin prick test results (atopic group) and 30 healthy subjects (control group) were included in this study. Tympanometric tests were performed in all participants, and the results were classified as type A to C. Mastoid cell volumes were measured by three-dimensional temporal computed tomography. Both the right and left mastoid volumes were significantly lower in the atopic group than in the control group. Tympanogram types among all participants showed that the number of individuals with abnormal tympanograms was significantly higher in the atopic group than in the control group. Moreover, the presence of atopy was found to be associated with an almost 4.5-fold increased risk of having an abnormal tympanogram. Individuals with abnormal tympanograms (type BB or CC) demonstrated significantly lower right and left mastoid volumes than did individuals with normal type A tympanograms. Atopic individuals demonstrated significantly lower right and left mastoid volumes than did subjects in the control group. This study suggests a direct association between atopy and mastoid cell volumes. It was found that the mastoid cell systems of atopic individuals are less pneumatized, and tympanometric measurements are worse in atopic subjects. Therefore, the authors suggest that when a medical or surgical treatment is planned for ear disease in atopic individuals, atopy is an important factor that should be taken into consideration.